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Structure of the human marker of self 5-transmembrane receptor CD47.
Fenalti, Gustavo; Villanueva, Nicolas; Griffith, Mark; Pagarigan, Barbra; Lakkaraju, Sirish Kaushik; Huang, Richard Y-C; Ladygina, Nadia; Sharma, Alok; Mikolon, David; Abbasian, Mahan; Johnson, Jeffrey; Hadjivassiliou, Haralambos; Zhu, Dan; Chamberlain, Philip P; Cho, Ho; Hariharan, Kandasamy.
Afiliación
  • Fenalti G; Molecular Structure and Design, Bristol Myers Squibb, San Diego, CA, USA. Gustavo.Fenalti@bms.com.
  • Villanueva N; Molecular Structure and Design, Bristol Myers Squibb, San Diego, CA, USA.
  • Griffith M; Protein Homeostasis, Bristol Myers Squibb, San Diego, CA, USA.
  • Pagarigan B; Molecular Structure and Design, Bristol Myers Squibb, San Diego, CA, USA.
  • Lakkaraju SK; Molecular Structure and Design, Bristol Myers Squibb, Princeton, NJ, USA.
  • Huang RY; Pharmaceutical Candidate Optimization, Nonclinical Research and Development, Bristol Myers Squibb, Princeton, NJ, USA.
  • Ladygina N; Pharmacology, Bristol Myers Squibb, San Diego, CA, USA.
  • Sharma A; Molecular Structure and Design, Bristol Myers Squibb, Princeton, NJ, USA.
  • Mikolon D; Discovery Biotherapeutics, Bristol Myers Squibb, San Diego, CA, USA.
  • Abbasian M; Discovery Biotherapeutics, Bristol Myers Squibb, San Diego, CA, USA.
  • Johnson J; Discovery Biotherapeutics, Bristol Myers Squibb, San Diego, CA, USA.
  • Hadjivassiliou H; Discovery Biotherapeutics, Bristol Myers Squibb, San Diego, CA, USA.
  • Zhu D; Discovery Biotherapeutics, Bristol Myers Squibb, San Diego, CA, USA.
  • Chamberlain PP; Protein Homeostasis, Bristol Myers Squibb, San Diego, CA, USA.
  • Cho H; Discovery Biotherapeutics, Bristol Myers Squibb, San Diego, CA, USA.
  • Hariharan K; Discovery Biotherapeutics, Bristol Myers Squibb, San Diego, CA, USA.
Nat Commun ; 12(1): 5218, 2021 09 01.
Article en En | MEDLINE | ID: mdl-34471125
CD47 is the only 5-transmembrane (5-TM) spanning receptor of the immune system. Its extracellular domain (ECD) is a cell surface marker of self that binds SIRPα and inhibits macrophage phagocytosis, and cancer immuno-therapy approaches in clinical trials are focused on blocking CD47/SIRPα interaction. We present the crystal structure of full length CD47 bound to the function-blocking antibody B6H12. CD47 ECD is tethered to the TM domain via a six-residue peptide linker (114RVVSWF119) that forms an extended loop (SWF loop), with the fundamental role of inserting the side chains of W118 and F119 into the core of CD47 extracellular loop region (ECLR). Using hydrogen-deuterium exchange and molecular dynamics simulations we show that CD47's ECLR architecture, comprised of two extracellular loops and the SWF loop, creates a molecular environment stabilizing the ECD for presentation on the cell surface. These findings provide insights into CD47 immune recognition, signaling and therapeutic intervention.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores Inmunológicos / Biomarcadores / Proteínas Portadoras / Antígeno CD47 Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores Inmunológicos / Biomarcadores / Proteínas Portadoras / Antígeno CD47 Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido